The immunobiology of experimental infection in mice with Trypanosoma cruzi is quite complex. The development of immune resistance to this parasite requires the participation of both humoral and cellular immune responses during infection. Previous investigations by the principal investigator of this proposal have demonstrated the occurrance of a significant elevation of natural killer (NK) cell activity and the stimulation of cytotoxic activity mediated by a cell population with shared properties of NK and T lymphocytes against several tumor cell lines. Preliminary experiments suggest that murine NK cells have cytotoxic activity against epimastigotes as well as blood-form trypomastigotes of T. cruzi. The activity against epimastigotes as well as culture-derived trypomastigotes was significantly increased when parasite-specific antibodies were added to cytotoxicity assay cultures. Furthermore, agents which increased NK cell activity against certain tumore cell lines also increased destruction of T. cruzi. We propose to investigate the cytotoxic activity of murine NK cells against various extracellular forms of this parasite using indirect (microscopic examination) and direct (radioisotope release) cytotoxicity assays. These studies will include a detailed examination of NK cell activity against the parasite during the course of murine infection (acute and chronic phases); the contribution of NK cells from normal or infected mice to antibody-dependent, cellular cytotoxicity (ADCC) against T. cruzi; the effect of adoptive transfer of augmented NK cell activity on murine resistance to infection as well as the influence various biological response modifying agents which alter NK cell activity on resistance; and the possible mechanisms responsible for the differential susceptibility of epimastigotes and culture-derived trypomastigotes to NK cell activity. These studies will be done using several inbred strains of mice with differential resistance to infection.